The gut responds to a large variety of stimuli, including nutrients, chemicals, mechanical factors, hormones and micro-organisms {Dockray, 2003, J Physiol Pharmacol, 54 Suppl 4, 9-17}. Many of these stimuli are detected through specific receptors that are expressed on the luminal surface of the gastrointestinal tract. In particular, multiple receptors are expressed in the small intestine that recognize sugars.
Sugar transport across the intestinal membranes is tightly regulated and is mediated by a specific set of receptors (reviewed in {Drozdowski and Thomson, 2006, World J Gastroenterol, 12, 1657-70}). Dietary glucose crosses the apical membrane of the enterocyte in the small intestine by the Na+/glucose cotransporter (SGLT1). Dietary fructose is transported across the apical membrane by the facilitative transporter GLUT5. The transporter GLUT2 is important in transporting glucose, particularly at high concentrations {Drozdowski and Thomson, 2006, World J Gastroenterol, 12, 1657-70}. The transporter GLUT7 is also expressed in the small intestine {Li et al., 2004, Am J Physiol Gastrointest Liver Physiol, 287, G236-42}.
GLUT2 expression on the apical surface of enterocytes is regulated by both SGLT1 {Kellett and Brot-Laroche, 2005, Diabetes, 54, 3056-62} and by sweet taste receptors {Mace et al., 2007, J Physiol}. At high glucose concentrations, GLUT2 is inserted into the apical membrane, thereby providing a cooperative mechanism by which glucose absorptive capacity is rapidly and precisely matched to dietary intake immediately after a meal {Mace et al., 2007, J Physiol}. GLUT2 has been identified as a potential therapeutic target for small molecule inhibitors, and quercitin and similar flavonoids have been shown to be GLUT2 inhibitors {Kwon et al., 2007, FASEB J, 21, 366-77}. GLUT2 inhibition could be therapeutic for diabetes and/or obesity.
The intestine expresses taste receptors on the epithelial cells of the stomach and duodenum known as brush cells {Hofer et al., 1996, Proc Natl Acad Sci U S A, 93, 6631-4} {Bezencon et al., 2007, Chem Senses, 32, 41-9}. Taste receptors are also expressed on the enteroendocrine cells of the intestinal tract {Masuho et al., 2005, Chem Senses, 30, 281-90}. The sweet taste receptors (T1Rs), including T1R1, T1R2 and T1R3, belong to the guanine nucleotide regulatory protein (G protein)-coupled receptor (GPCR) superfamily. The receptors have a long extracellular NH2-terminal segment, seven transmembrane a-helices, three extracellular loops, three cytoplasmic loops and a COOH-terminal segment. The T1Rs function as molecular complexes, with the heterodimeric T1R2/T1R3 receptor binding to sweet stimuli while the T1R1/T1R3 complex recognizes amino acids {Rozengurt, 2006, Am J Physiol Gastrointest Liver Physiol, 291, G171-7}.
Polyclonal antibodies have been described that are specific for the receptors present in the GI tract as research agents useful in the detection of the receptor of interest by immunostaining. For example, antibodies have been described to alpha-gustducin, the GTP-binding subunit of taste receptors {Hofer et al., 1996, Proc Natl Acad Sci U S A, 93, 6631-4}. Several antibodies specific for SGLT1, GLUT5, GLUT2, TAS1R1, TAS1R2, TAS1R3 and T2R1 are commercially available as research reagents for the detection of the receptor of interest. However, oral delivery of protein therapeutics to modulate cellular receptors located in the lumen of the GI tract to treat various conditions is an unexplored area. Compositions and methods for administration of therapeutic antibodies directly to the GI tract to target apical intestinal receptors to treat conditions modulated by such target receptors, are therefore needed.